Retinol dehydrogenase

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Retinol dehydrogenase
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EC no. 1.1.1.105
CAS no. 9033-53-8
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In enzymology, a retinol dehydrogenase (RDH) (EC 1.1.1.105) is an enzyme that catalyzes the chemical reaction

Contents

retinol + NAD+ retinal + NADH + H+

Sometimes, in addition to or along with NAD+, NADP+ can act as a preferred cofactor in the reaction as well. The substrate of the enzyme can be all-trans- or -cis- retinol. There are at least over 20 different isolated enzymes with RDH activity to date. [1] Thus, the two substrates of this enzyme are retinol and NAD+, whereas its 3 products are retinal, NADH (or NADPH in the case where NADP+ is a cofactor), and H+. [1]

This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-OH group of donor with NAD+ or NADP+ as acceptor. The systematic name of this enzyme class is retinol:NAD+ oxidoreductase. Other names in common use include retinol (vitamin A1) dehydrogenase, MDR, microsomal retinol dehydrogenase, all-trans retinol dehydrogenase, retinal reductase, and retinene reductase. This enzyme participates in retinol metabolism. [2] Occasionally, the literature refers to retinol dehydrogenase as an enzyme that oxidizes retinol in general, such as class IV alcohol dehydrogenase (ADH4), which reportedly is the most efficient retinol oxidation in the human alcohol dehydrogenase (ADH) family. [3] [4]

Structure

Image 1: Wild-type human sigma (class IV) alcohol dehydrogenase (1D1S) has retinol dehydrogenase activity. Zinc molecules are depicted as red balls, while NAD molecules are purple. Note that the enzyme exists as two protein units in this figure. (PDB file from RCSB) 1D1S redZn violetNAD dimer.png
Image 1: Wild-type human sigma (class IV) alcohol dehydrogenase (1D1S) has retinol dehydrogenase activity. Zinc molecules are depicted as red balls, while NAD molecules are purple. Note that the enzyme exists as two protein units in this figure. (PDB file from RCSB)
Image 2: Wild-type human sigma (class IV) alcohol dehydrogenase (1D1S). Retinols will bind between the catalytic zinc molecules (red balls) and the NAD molecule (purple). (PDB file from RCSB) 1D1S redZn violetNAD zoom.png
Image 2: Wild-type human sigma (class IV) alcohol dehydrogenase (1D1S). Retinols will bind between the catalytic zinc molecules (red balls) and the NAD molecule (purple). (PDB file from RCSB)

As one of the most important RDH, 11-cis-retinol dehydrogenase catalyzes the 11-cis retinaldehyde (the most common visual pigments in higher animals) formation. The enzyme is mainly expressed in the retinal pigment epithelium ( RPE ) and is part of short-chain dehydrogenase (SDR) / reductase superfamily. The integral membrane enzyme is anchored to the membranes by its two hydrophobic chains. The catalytic domain of 11-cis-retinol dehydrogenase is restricted to the lumenal compartment, suggesting its origin from compartmentalized process. 11-cis-retinol dehydrogenase is also mainly associated to the smooth endoplasmic reticulum of RPE cells. [7] The 32-kDa integral membrane protein protein (p32) was found to act as the stereospecific 11-cis-retinol dehydrogenase in the presence of NAD+ cofactor, and p32 catalyzes the biosynthesis of 11-cis retinal commonly found visual chromophore. [8]

One of the widely studied genes of retinol dehydrogenase RDH12, which encodes retinol dehydrogenase is part of the superfamily of short-chained alcohol dehydrogenases and reductases. RDH12 is mainly expressed in neuroretina and is composed of 7 exons encoding a 360-amino acid peptide. [9]

Zinc molecules serve as the ligand cofactor with the cofactor NAD. The retinol will interact with the enzyme at the area between those two cofactors. [6]

However, not all retinol dehydrogenases in visual cycle are identified, and this remains challenging to scientists due to the overlapping expressions and activity redundancy among two large RDH and RDH-like producing classes: microsomal short-chain dehydrogenase/reductase and cytosolic medium-chain alcohol dehydrogenases. [10]

In Bovine, retinol dehydrogenase is found as a part of retinal rod outer segments and shows difficulty when separating from membrane. Its Stokes radius is 8.5 nm in Lubrol 12A9 mixed micelle. [11]

Function

Retinoid dehydrogenases/reductases (oxidoreductases), including retinol dehydrogenase, catalyze the key oxidation-reduction reactions in the visual cycle, converting vitamin A to 11-cis retinal, which is the chromophore of the rod and cone photoreceptors. It is believed that RDHs at rod and cone are different, but related and can catalyze the same reaction. RDH12 is the primary enzyme that reduces all-trans retinal released from bleached photopigments during recovery phase in the visual cycle. The RDH12 enzyme can use either cis or trans retinoid isomers as substrates and can also function as both dehydrogenase (i.e. retinol to retinal) and reductase (i.e. retinal to retinol). [12] [13]

The conversion of retinol to retinal is the rate-limiting step in the retinoic acid biosynthesis. In vertebrates, the retinoic acid is the ligand that controls nuclear receptor signaling pathway, which is responsible for growth and development as well as epithelial maintenance, therefore can be used for cancer and acne treatment. In human, ADH4 can exhibit at least 10 folds higher Vmax/Km than other ADH. [4]

Image 3: The visual phototransduction cycle yields 11-cis-retinal from 11-cis-retinol using 11-cis-retinol dehydrogenase. Visual cycle adapted v3.png
Image 3: The visual phototransduction cycle yields 11-cis-retinal from 11-cis-retinol using 11-cis-retinol dehydrogenase.

Some retinol dehydrogenases are in extra-ocular tissues, such as human retinol dehydrogenase-4 (RoDH-4), which converts retinol and 1-cis-retinol to different aldehydes in liver and skin. It was also found that 13-cis-retinoic acid (isotretinoin), 3,4-didehydroretinoic acid, and 3,4-didehydroretinol can act as competitive inhibitor of the 3α-hydroxysteroid dehydrogenase oxidative activity of the enzyme. This can potentially explain how isotretinoin, the active ingredient is Roaccutane (Accutane), can suppress sebaceous glands and be used for severe acne treatment. [15]

Disease relevance

The missense mutation in gene rdh5, which codes for microsomal 11-cis-retinol dehydrogenase (RDH5), causes fundus albipunctatus, whose symptoms include retinal white-spot accumulation, stationary night blindness caused by delay in cone and rod photopigment regeneration, and elderly cone dystrophy. [1] [16]

At least 20 mutations in rdh12 gene, which encodes retinol dehydrogenase, can be associated to diseases, including severe and early-onset autosomal recessive retinal dystrophy (arRD), or Leber congenital amaurosis. Patients suffer from cone and rod malfunction since childhood and develop legal blindness when reaching adulthood. This suggests that RDH12 might play a central role in the visual cycle and can be a promising therapeutic target. [9] [12] A possible mechanism of the accelerated degradation among RDH12 mutants is the polyubiquitination by cytosolic ubiquitin ligases and subsequent degradation by proteosome. Its conformation aberration provokes the aforementioned accelerated degradation. [17]

Related Research Articles

<span class="mw-page-title-main">Vitamin A</span> Essential nutrient

Vitamin A is a fat-soluble vitamin and an essential nutrient for animals. The term "vitamin A" encompasses a group of chemically related organic compounds that includes retinol, retinal, retinoic acid, and several provitamin (precursor) carotenoids, most notably beta-carotene. Vitamin A has multiple functions: it is essential for embryo development and growth, for maintenance of the immune system, and for vision, where it combines with the protein opsin to form rhodopsin – the light-absorbing molecule necessary for both low-light and color vision.

<span class="mw-page-title-main">Retinol</span> Chemical compound

Retinol, also called vitamin A1, is a fat-soluble vitamin in the vitamin A family that is found in food and used as a dietary supplement. Retinol or other forms of vitamin A are needed for vision, cellular development, maintenance of skin and mucous membranes, immune function and reproductive development. Dietary sources include fish, dairy products, and meat. As a supplement it is used to treat and prevent vitamin A deficiency, especially that which results in xerophthalmia. It is taken by mouth or by injection into a muscle. As an ingredient in skin-care products, it is used to reduce wrinkles and other effects of skin aging.

<span class="mw-page-title-main">Retinal</span> Chemical compound

Retinal is a polyene chromophore. Retinal, bound to proteins called opsins, is the chemical basis of visual phototransduction, the light-detection stage of visual perception (vision).

<span class="mw-page-title-main">Retinoic acid</span> Metabolite of vitamin A

Retinoic acid (used simplified here for all-trans-retinoic acid) is a metabolite of vitamin A1 (all-trans-retinol) that mediates the functions of vitamin A1 required for growth and development. All-trans-retinoic acid is required in chordate animals, which includes all higher animals from fish to humans. During early embryonic development, all-trans-retinoic acid generated in a specific region of the embryo helps determine position along the embryonic anterior/posterior axis by serving as an intercellular signaling molecule that guides development of the posterior portion of the embryo. It acts through Hox genes, which ultimately control anterior/posterior patterning in early developmental stages.

<span class="mw-page-title-main">Aldose reductase</span> Enzyme

In enzymology, aldose reductase is a cytosolic NADPH-dependent oxidoreductase that catalyzes the reduction of a variety of aldehydes and carbonyls, including monosaccharides. It is primarily known for catalyzing the reduction of glucose to sorbitol, the first step in polyol pathway of glucose metabolism.

The visual cycle is a process in the retina that replenishes the molecule retinal for its use in vision. Retinal is the chromophore of most visual opsins, meaning it captures the photons to begin the phototransduction cascade. When the photon is absorbed, the 11-cis retinal photoisomerizes into all-trans retinal as it is ejected from the opsin protein. Each molecule of retinal must travel from the photoreceptor cell to the RPE and back in order to be refreshed and combined with another opsin. This closed enzymatic pathway of 11-cis retinal is sometimes called Wald's visual cycle after George Wald (1906–1997), who received the Nobel Prize in 1967 for his work towards its discovery.

In enzymology, an alcohol dehydrogenase [NAD(P)+] (EC 1.1.1.71) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Glyoxylate reductase</span> Enzyme

Glyoxylate reductase, first isolated from spinach leaves, is an enzyme that catalyzes the reduction of glyoxylate to glycolate, using the cofactor NADH or NADPH.

<span class="mw-page-title-main">Formaldehyde dehydrogenase</span>

In enzymology, a formaldehyde dehydrogenase (EC 1.2.1.46) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Retinal dehydrogenase</span>

In enzymology, a retinal dehydrogenase, also known as retinaldehyde dehydrogenase (RALDH), catalyzes the chemical reaction converting retinal to retinoic acid. This enzyme belongs to the family of oxidoreductases, specifically the class acting on aldehyde or oxo- donor groups with NAD+ or NADP+ as acceptor groups, the systematic name being retinal:NAD+ oxidoreductase. This enzyme participates in retinol metabolism. The general scheme for the reaction catalyzed by this enzyme is:

<span class="mw-page-title-main">NAD(P)H dehydrogenase (quinone)</span>

In enzymology, a NAD(P)H dehydrogenase (quinone) (EC 1.6.5.2) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">RPE65</span> Protein-coding gene in humans

Retinal pigment epithelium-specific 65 kDa protein, also known as retinoid isomerohydrolase, is an enzyme of the vertebrate visual cycle that is encoded in humans by the RPE65 gene. RPE65 is expressed in the retinal pigment epithelium and is responsible for the conversion of all-trans-retinyl esters to 11-cis-retinol during phototransduction. 11-cis-retinol is then used in visual pigment regeneration in photoreceptor cells. RPE65 belongs to the carotenoid oxygenase family of enzymes.

<span class="mw-page-title-main">RDH5</span> Protein-coding gene in the species Homo sapiens

11-cis retinol dehydrogenase is an enzyme that in humans is encoded by the RDH5 gene.

<span class="mw-page-title-main">RDH11</span> Protein-coding gene in the species Homo sapiens

Retinol dehydrogenase 11 is an enzyme that in humans is encoded by the RDH11 gene.

<span class="mw-page-title-main">RDH12</span> Protein-coding gene in the species Homo sapiens

Retinol dehydrogenase 12 is an enzyme that in humans is encoded by the RDH12 gene.

<span class="mw-page-title-main">DHRS9</span> Protein-coding gene in the species Homo sapiens

Dehydrogenase/reductase SDR family member 9 is an enzyme that in humans is encoded by the DHRS9 gene.

<span class="mw-page-title-main">HSD17B6</span>

Hydroxysteroid 17-beta dehydrogenase 6 is an enzyme that in humans is encoded by the HSD17B6 gene.

<span class="mw-page-title-main">RDH8</span> Protein-coding gene in the species Homo sapiens

Retinol dehydrogenase 8 is an enzyme that in humans is encoded by the RDH8 gene.

<span class="mw-page-title-main">Lecithin retinol acyltransferase</span> Mammalian protein found in Homo sapiens

Lecithin retinol acyltransferase is an enzyme that in humans is encoded by the LRAT gene.

<span class="mw-page-title-main">RDH13</span> Protein-coding gene in the species Homo sapiens

Retinol dehydrogenase 13 (all-trans/9-cis) is a protein that in humans is encoded by the RDH13 gene. This gene encodes a mitochondrial short-chain dehydrogenase/reductase, which catalyzes the reduction and oxidation of retinoids. The encoded enzyme may function in retinoic acid production and may also protect the mitochondria against oxidative stress. Alternatively spliced transcript variants have been described.

References

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